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Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease.

Zhang L, Zhang S, Maezawa I, Trushin S, Minhas P, Pinto M, Jin LW, Prasain K, Nguyen TD, Yamazaki Y, Kanekiyo T, Bu G, Gateno B, Chang KO, Nath KA, Nemutlu E, Dzeja P, Pang YP, Hua DH, Trushina E - EBioMedicine (2015)

Bottom Line: Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress.Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice.Our results suggest metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.

ABSTRACT

Development of therapeutic strategies to prevent Alzheimer's Disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.

No MeSH data available.


Related in: MedlinePlus

CP2 restores axonal trafficking and increases levels of synaptic markers and BDNF.(A) Visualization of mitochondria in live neuron using TMRM and LSM 510 confocal microscope, 100 × oil DIC lens (1.4 NA). Scale bar, 10 mm. (B, C) Representative kymographs showing reduced axonal transport with primarily stationary mitochondria (horizontal lines) in APP/PS1 neurons (B) and significantly greater mitochondrial motility (diagonal lines) in neurons from APP/PS1 mice treated with CP2 in utero (C). Neurons were plated from P1 animals and imaged after 7 DIC. Data analysis for these experiments is presented in D and E. (D) CP2 restores mitochondrial trafficking in anterograde and retrograde directions in neurons from APP/PS1 (A/P, n = 5) and PS1 (n = 5) P1 pups born from the CP2-treated F2 mice. (E) Mitochondria in neurons from newborn mice treaded with CP2 in utero moved more frequently. All values are presented as mean ± standard error. *P < 0.05; **P < 0.01; ***P < 0.001. (F) Western blotting in brain extracts from APP/PS1 (n = 3) mice treated with CP2 (25 mg/kg/day, 2 months) shows an increase in synaptophysin, BDNF and pAMPK compared to untreated APP/PS1 animals (n = 3). (G–I) Fold differences in protein levels from (F) normalized to tubulin using densitometry. *P < 0.05. (J) Data interpretation.
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f0035: CP2 restores axonal trafficking and increases levels of synaptic markers and BDNF.(A) Visualization of mitochondria in live neuron using TMRM and LSM 510 confocal microscope, 100 × oil DIC lens (1.4 NA). Scale bar, 10 mm. (B, C) Representative kymographs showing reduced axonal transport with primarily stationary mitochondria (horizontal lines) in APP/PS1 neurons (B) and significantly greater mitochondrial motility (diagonal lines) in neurons from APP/PS1 mice treated with CP2 in utero (C). Neurons were plated from P1 animals and imaged after 7 DIC. Data analysis for these experiments is presented in D and E. (D) CP2 restores mitochondrial trafficking in anterograde and retrograde directions in neurons from APP/PS1 (A/P, n = 5) and PS1 (n = 5) P1 pups born from the CP2-treated F2 mice. (E) Mitochondria in neurons from newborn mice treaded with CP2 in utero moved more frequently. All values are presented as mean ± standard error. *P < 0.05; **P < 0.01; ***P < 0.001. (F) Western blotting in brain extracts from APP/PS1 (n = 3) mice treated with CP2 (25 mg/kg/day, 2 months) shows an increase in synaptophysin, BDNF and pAMPK compared to untreated APP/PS1 animals (n = 3). (G–I) Fold differences in protein levels from (F) normalized to tubulin using densitometry. *P < 0.05. (J) Data interpretation.

Mentions: We previously reported that inhibition of axonal trafficking was detected early in embryonic neurons from PS1 and APP/PS1 mice (Trushina et al., 2012). Increased levels of Aβ, pTau and activated GSK3β are implicated in the development of axonal trafficking dysfunction in AD (Vicario-Orri et al., 2015). We next explored whether changes induced by modulation of complex I activity positively affected axonal transport. Using established methodology (Trushina et al., 2004, 2012) (Fig. 7A–C), we evaluated mitochondrial motility in neurons from F2 pups treated with CP2 in utero (Fig. 1B). Visualization of mitochondrial dynamics in live neurons revealed lack of trafficking inhibition in APP/PS1 and PS1 mice in both anterograde and retrograde directions (Fig. 7B–D) and significant increase in motile organelles (Fig. 7E). Since CP2 levels were similar in the brain tissue of neonatal F2 and adult FAD animals (Table S1, P1), we examined whether axonal trafficking was also improved in adult mice in vivo by measuring levels of brain-derived neurotrophic factor (BDNF) in APP/PS1 mice treated with CP2 for 2 months (Fig. 7F). BDNF provides an essential support for synaptic function, plasticity and neuronal survival. It is delivered to the cell body via retrograde trafficking, and its reduced availability is among the most devastating consequences of axonal trafficking inhibition (Poon et al., 2011). Restoration of axonal transport and improved BDNF support could positively affect levels of synaptic proteins. Indeed, we found significant increase in synaptophysin and BDNF in brain tissue of CP2-treated APP/PS1 mice (Fig. 7F–I) consistent with preserved cognitive function.


Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease.

Zhang L, Zhang S, Maezawa I, Trushin S, Minhas P, Pinto M, Jin LW, Prasain K, Nguyen TD, Yamazaki Y, Kanekiyo T, Bu G, Gateno B, Chang KO, Nath KA, Nemutlu E, Dzeja P, Pang YP, Hua DH, Trushina E - EBioMedicine (2015)

CP2 restores axonal trafficking and increases levels of synaptic markers and BDNF.(A) Visualization of mitochondria in live neuron using TMRM and LSM 510 confocal microscope, 100 × oil DIC lens (1.4 NA). Scale bar, 10 mm. (B, C) Representative kymographs showing reduced axonal transport with primarily stationary mitochondria (horizontal lines) in APP/PS1 neurons (B) and significantly greater mitochondrial motility (diagonal lines) in neurons from APP/PS1 mice treated with CP2 in utero (C). Neurons were plated from P1 animals and imaged after 7 DIC. Data analysis for these experiments is presented in D and E. (D) CP2 restores mitochondrial trafficking in anterograde and retrograde directions in neurons from APP/PS1 (A/P, n = 5) and PS1 (n = 5) P1 pups born from the CP2-treated F2 mice. (E) Mitochondria in neurons from newborn mice treaded with CP2 in utero moved more frequently. All values are presented as mean ± standard error. *P < 0.05; **P < 0.01; ***P < 0.001. (F) Western blotting in brain extracts from APP/PS1 (n = 3) mice treated with CP2 (25 mg/kg/day, 2 months) shows an increase in synaptophysin, BDNF and pAMPK compared to untreated APP/PS1 animals (n = 3). (G–I) Fold differences in protein levels from (F) normalized to tubulin using densitometry. *P < 0.05. (J) Data interpretation.
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Related In: Results  -  Collection

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f0035: CP2 restores axonal trafficking and increases levels of synaptic markers and BDNF.(A) Visualization of mitochondria in live neuron using TMRM and LSM 510 confocal microscope, 100 × oil DIC lens (1.4 NA). Scale bar, 10 mm. (B, C) Representative kymographs showing reduced axonal transport with primarily stationary mitochondria (horizontal lines) in APP/PS1 neurons (B) and significantly greater mitochondrial motility (diagonal lines) in neurons from APP/PS1 mice treated with CP2 in utero (C). Neurons were plated from P1 animals and imaged after 7 DIC. Data analysis for these experiments is presented in D and E. (D) CP2 restores mitochondrial trafficking in anterograde and retrograde directions in neurons from APP/PS1 (A/P, n = 5) and PS1 (n = 5) P1 pups born from the CP2-treated F2 mice. (E) Mitochondria in neurons from newborn mice treaded with CP2 in utero moved more frequently. All values are presented as mean ± standard error. *P < 0.05; **P < 0.01; ***P < 0.001. (F) Western blotting in brain extracts from APP/PS1 (n = 3) mice treated with CP2 (25 mg/kg/day, 2 months) shows an increase in synaptophysin, BDNF and pAMPK compared to untreated APP/PS1 animals (n = 3). (G–I) Fold differences in protein levels from (F) normalized to tubulin using densitometry. *P < 0.05. (J) Data interpretation.
Mentions: We previously reported that inhibition of axonal trafficking was detected early in embryonic neurons from PS1 and APP/PS1 mice (Trushina et al., 2012). Increased levels of Aβ, pTau and activated GSK3β are implicated in the development of axonal trafficking dysfunction in AD (Vicario-Orri et al., 2015). We next explored whether changes induced by modulation of complex I activity positively affected axonal transport. Using established methodology (Trushina et al., 2004, 2012) (Fig. 7A–C), we evaluated mitochondrial motility in neurons from F2 pups treated with CP2 in utero (Fig. 1B). Visualization of mitochondrial dynamics in live neurons revealed lack of trafficking inhibition in APP/PS1 and PS1 mice in both anterograde and retrograde directions (Fig. 7B–D) and significant increase in motile organelles (Fig. 7E). Since CP2 levels were similar in the brain tissue of neonatal F2 and adult FAD animals (Table S1, P1), we examined whether axonal trafficking was also improved in adult mice in vivo by measuring levels of brain-derived neurotrophic factor (BDNF) in APP/PS1 mice treated with CP2 for 2 months (Fig. 7F). BDNF provides an essential support for synaptic function, plasticity and neuronal survival. It is delivered to the cell body via retrograde trafficking, and its reduced availability is among the most devastating consequences of axonal trafficking inhibition (Poon et al., 2011). Restoration of axonal transport and improved BDNF support could positively affect levels of synaptic proteins. Indeed, we found significant increase in synaptophysin and BDNF in brain tissue of CP2-treated APP/PS1 mice (Fig. 7F–I) consistent with preserved cognitive function.

Bottom Line: Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress.Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice.Our results suggest metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Mayo Clinic Rochester, MN 55905, USA.

ABSTRACT

Development of therapeutic strategies to prevent Alzheimer's Disease (AD) is of great importance. We show that mild inhibition of mitochondrial complex I with small molecule CP2 reduces levels of amyloid beta and phospho-Tau and averts cognitive decline in three animal models of familial AD. Low-mass molecular dynamics simulations and biochemical studies confirmed that CP2 competes with flavin mononucleotide for binding to the redox center of complex I leading to elevated AMP/ATP ratio and activation of AMP-activated protein kinase in neurons and mouse brain without inducing oxidative damage or inflammation. Furthermore, modulation of complex I activity augmented mitochondrial bioenergetics increasing coupling efficiency of respiratory chain and neuronal resistance to stress. Concomitant reduction of glycogen synthase kinase 3β activity and restoration of axonal trafficking resulted in elevated levels of neurotrophic factors and synaptic proteins in adult AD mice. Our results suggest metabolic reprogramming induced by modulation of mitochondrial complex I activity represents promising therapeutic strategy for AD.

No MeSH data available.


Related in: MedlinePlus